3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) Lyase Deficiency

CASE REPORT

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Department of Pediatrics, Division of Pediatric Nutrition and Metabolism, Erciyes University Faculty of Medicine, Kayseri, Turkey Submitted 30.10.2017 Accepted 05.02.2018 Available Online Date

03.09.2018 Correspondence Pembe Soylu Üstkoyuncu

Department of Pediatrics, Division of Pediatric Nutrition and Metabolism, Erciyes University Faculty of Medicine, Kayseri, Turkey Phone: +90 3522076666 e.mail:

[email protected]

©Copyright 2018 by Erciyes University Faculty of Medicine - Available online at www.

erciyesmedj.com

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) Lyase Deficiency

Pembe Soylu Üstkoyuncu, Mustafa Kendirci, Songül Gökay, Fatih Kardaş

ABSTRACT

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency is an autosomal recessive disorder involving ketone body syn- thesis and leucine degradation. It is characterized by vomiting, hypotension, lethargy, metabolic acidosis, and non-ketotic hy- poglycemia. A 3-month-old girl presented with clinical symptoms of vomiting and drowsiness. Her clinical findings included hypoglycemia, hyperammonemia, metabolic acidosis, and elevated alanine aminotransferase and aspartate aminotransferase levels. The level of C5OH acylcarnitine was elevated as determined by liquid chromatography–tandem mass spectrometry.

The levels of 3-methylglutaric acid, 3-methylglutaconic acid, 3-OH isovaleric acid, glutaric acid, and 3-hydroxy-3-methyl- glutaric acid were found to be elevated in the analysis of urinary organic acids. According to these clinical and laboratory findings, she was diagnosed with HMG-CoA lyase deficiency. Carnitine treatment and protein- and fat-restricted and carbo- hydrate-rich diet were started. HMG-CoA lyase deficiency is one of the disorders that should be considered in the presence of non-ketotic hypoglycemia, metabolic acidosis, and hyperammonemia.

Keywords: HMG-CoA lyase deficiency, metabolic acidosis, non-ketotic hypoglycemia Erciyes Med J 2018; 40(3): 169-71 • DOI: 10.5152/etd.2018.0128

INTRODUCTION

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency is a rare autosomal recessive congenital defect of ketone body synthesis and leucine degradation. The HMG-CoA lyase enzyme is localized in the mito- chondria and peroxisomes and converts HMG-CoA to acetyl CoA and acetoacetate at the last step of leucine catabolism (Figure 1) (1).

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency leads to a reduced ability to synthesize ke- tones, which are the primary energy source of the brain when glucose is unavailable. In 1976, Faull et al. (2) first described the disorder in a 7-month-old boy with metabolic acidosis and hypoglycemia.

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency is usually clinically evident during infancy and is characterized by vomiting, hypotonia, lethargy, metabolic acidosis, non-ketotic hypoglycemia, and Reye- like syndrome. Patients with this disorder are usually normal except for recurrent metabolic attacks that can be triggered by infection, starvation, and excessive physical exercise (1, 3). These attacks can cause deaths in 20% of cases and serious long-term morbidities such as psychomotor retardation, epilepsy, hepatic steatosis, pancreatitis, or dilated cardiomyopathy (3, 4).

Although the organic acid profile is essentially diagnostic, enzyme deficiency can be detected in cultured fibroblasts, or the diagnosis can be confirmed by molecular genetic analysis of the HMGCL gene (1). There are a few reports that demonstrate the clinical findings of this condition (2-6).

CASE REPORT

A 3-month-old girl presented with vomiting and drowsiness. She was born after an uneventful pregnancy by spon- taneous vaginal delivery. She weighed 3000 g. Her prenatal, obstetric, and family histories were unremarkable.

She was hospitalized owing to hypoglycemia and elevated alanine aminotransferase (ALT) and aspartate amino- transferase (AST) levels 1 month ago prior to the last hospital admission. She was discharged after her symptoms improved with supportive treatment.

Her body weight, height, and head circumference were 5.2 kg (10% to 25% percentile), 58 cm (10% to 25%

percentile), and 40 cm (50% percentile), respectively. She was hypotonic, hypoactive, and lethargic, and she

Cite this article as:

Soylu Üstkoyuncu P, Kendirci M, Gökay S, Kardaş F. 3-Hydroxy- 3-methylglutaryl-CoA (HMG-CoA) lyase defici- ency. Erciyes Med J 2018;

40(3): 169-71.

had hepatomegaly. Her liver edge was 5 cm below the right costal margin.

Metabolic tests were analyzed for inborn error of metabolism due to metabolic acidosis, hypoketotic hypoglycemia, hyperammone- mia, and elevated liver enzymes. Plasma amino acid and blood acylcarnitine levels were quantified using liquid chromatography–

tandem mass spectrometry, and urinary organic acid was analyzed using gas chromatography–mass spectrometry. Table 1 shows the laboratory findings of the patient.

The patient was diagnosed with HMG-CoA lyase deficiency accord- ing to the symptoms and laboratory findings. Sodium bicarbonate and fluid therapy with high dextrose were started for hypoglycemia and metabolic acidosis. Carnitine treatment (100 mg/kg/day) and carbohydrate-rich and protein- and fat-restricted diet were started.

Liver function tests were normal on day 20 after hospitalization.

The patient was hospitalized due to infections three times after the diagnosis, but Reye-like syndrome did not develop. Molecular ge- netic analysis could not be performed due to familial reasons. The patient is 4 years old now, and her intelligence is normal.

DISCUSSION

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase defi- ciency is a rare inborn error of leucine catabolism. The patient was admitted to the hospital with Reye-like syndrome and diagnosed with HMG-CoA lyase deficiency using organic acid analysis. Reye- like syndrome can be caused due to sepsis, intoxication, and various metabolic diseases. Inborn error of metabolism was considered in this patient because of lethargy, hepatomegaly, hypoglycemia, metabolic acidosis, elevated ALT and AST levels, and history of previous attack.

Patients with HMG-CoA lyase deficiency present with infection- or starvation-induced metabolic acidosis, hypoglycemia, vomiting, hyperammonemia, consciousness, hypotony, convulsions, hepato- megaly, and elevated ALT and AST levels (5, 6). Left ventricular cardiomyopathy and macrocephaly can be observed, but not fre- quently (4). Classical symptoms of the disorder were seen in our patient and were induced by infection.

Hyperinsulinism, endocrine deficiencies, and fatty acid oxidation defects can present along with hypoketotic hypoglycemia (7). En- docrine causes of hypoglycemia and fatty acid oxidation defects were ruled out in our patient.

White matter abnormalities, cerebral atrophy, mental retardation, and neurological disorders may occur due to prolonged hypogly- cemia and convulsions (8). The neurological development of our patient was normal, and she did not have any convulsion.

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Figure 1. Summary of ketone body metabolism. The HMG-CoA pathway of the ketone body formation is much more active in the liver than elsewhere. The ketone bodies, 3HB and AcAc, diffuse from liver mitochondria into circulation and then to the extrahepatic tissues including the brain. In extrahepatic tissues, SCOT and T2 mediate the production of acetyl CoA for use in energy production or synthesis.

HMG-CoA: 3-hydroxy-3-methylglutaryl-CoA, Ac-CoA: acetyl CoA, AcAc- CoA: acetoacetyl-CoA, TCA: tricarboxylic acid cycle, SCOT: succinyl-CoA-3- oxoacid CoA transferase, T2: beta-ketothiolase, 3HB: 3-hydroxybutyrate, FFA:

free fatty acid, mHS: mitochondrial HMG-CoA synthase, HL: HMG-CoA lyase, AcAc: acetoacetate.

Table 1. Laboratory findings of the patient

Non-specific tests Metabolic tests Blood gas analysis

Hb (g/dL) 9.5 Ammonia (mmol/L) 200 Blood pH 7.26

WBC (mm³) 5930 3-Methylglutaric acid (mmol/mol creatinine) 536 Bicarbonate level 9.4 PLT (mm³) 112,000 3-Methylglutaconic acid (mmol/mol creatinine) 3049 Base deficit −9 Glucose (mmol/L) 1.1 3-OH isovaleric acid (mmol/mol creatinine) 4026

ALT (IU/L) 534 Glutaric acid (mmol/mol creatinine) 494

AST (IU/L) 788 3-Hydroxy-3-methylglutaric acid (mmol/mol creatinine) 4210

Total/direct 1.6/1.3 C5OH acylcarnitine (μmol/L) 1.7

bilirubin (mg/dL) Urinary ketone (−)

Hb: hemoglobin, WBC: white blood cell, PLT: platelet, ALT: alanine aminotransferase, AST: aspartate aminotransferase

ALT level (n:10-49), AST level (n:0-34), ammonia level (n:11.2–35.4), C5OH acylcarnitine level (n:0–0.9), 3-methylglutaric acid level (n:0-9), 3-methylglutaconic acid level (n:0-9), 3-OH isovaleric acid level (n:0-46), glutaric acid level (N<2), and 3-hydroxy-3-methylglutaric acid level (n:11-36)

Some treatment options for patients with HMG-CoA lyase defi- ciency include intravenous fluid, sodium bicarbonate therapy, diet, and carnitine supplementation. Leucine- and oil-restricted and va- line-, isoleucine-, and carbohydrate-supplemented diet are recom- mended (9). The blood brain barrier is less selective during the early stages of development and can be more affected by neurotoxic metabolites. Ribas et al. (10) suggested that considering the abil- ity of l-carnitine to easily cross the blood brain barrier, l-carnitine supplementation may also be beneficial in preventing neurological damage derived from oxidative injury. l-Carnitine with leucine-re- stricted diet appears to play an important role in preventing neu- rological damage.

Although HMG-CoA lyase deficiency is a defined disorder among the causes of hypoglycemia in the infancy period, it has been ob- served to manifest in very few patients and is rarely considered in the differential diagnosis of hypoglycemia.

Informed Consent: Written informed consent was obtained from the par- ents of the patient who participated in this study.

Peer-review: Externally peer-reviewed.

Author Contributions: Conceived and designed the experiments or case:

PSÜ, MK. Analyzed the data: FK, SG. Wrote the paper: PSÜ. All authors have read and approved the final manuscript.

Conflict of Interest: The authors have no conflict of interest to declare.

Financial Disclosure: The authors declared that this study has received no financial support.

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Üstkoyuncu et al. HMG-CoA Lyase Deficiency Erciyes Med J 2018; 40(3): 169-71